Project Summary/Abstract Alcohol dependence is a widespread public health concern with limited treatment options available. A growing body of evidence supports binge intake of ethanol as a significant risk factor for the development of ethanol dependence. Additionally, this form of excessive ethanol intake is associated with negative health effects, such as heart disease and diabetes, and represents a significant portion of the financial burden induced by alcohol use within the United States. Our lab and others have extensively demonstrated the neuropeptide corticotropin releasing factor (CRF) plays an important role in modulating binge ethanol consumption. Further, alterations in the CRF system are known to play an important role in ethanol-related behaviors both following the development of ethanol-dependence and into withdrawal. Dissecting the specific role of CRF in binge drinking behavior in non-ethanol dependent animals therefore enables the discovery of treatments for this risky pattern of behavior and, further, provides important insights into initial ethanol related alterations of a system critically involved in the development and maintenance of ethanol-dependence. The role of CRF in ethanol-related behaviors within the extended amygdala has been the focus of numerous investigations. However, the role of CRF within regions critical to entraining these limbic regions and coordinating reward-directed/inhibiting inappropriate behaviors has gone essentially neglected. This proposal focuses on addressing this hole in the literature by examining the role of CRF within the medial prefrontal cortex (mPFC) in modulating binge ethanol consumption. The proposed studies will employ biochemical, pharmacogenetic, transgenic, and behavioral pharmacological approaches. The well-validated model of binge-like ethanol intake in rodents ?drinking in the dark? (DID) will be used throughout these experiments. For Aim 1, I will use the DID paradigm and immunohistochemistry and western blot techniques to assess whether 1 or 3-weeks of DID alter components of the mPFC CRF system (CRF, CRF receptor 1 and 2 (CRF1R/CRF2R), CRF-binding protein). For Aim 2, I will use designer receptor technology (viral injection of Cre-dependent DREADDs) along with CRH-IRES-Cre transgenic mice in the DID model to (1) determine whether ?silencing? CRF neurons (via activation of inhibitory DREADDs) in the mPFC decreases binge-like ethanol intake and associated blood ethanol concentrations (BECs) and (2) assess whether activation of CRF neurons (via excitatory DREADDs) in the in the mPFC decreases binge-like ethanol intake and associated BECs. For Aim 3, I will use behavioral pharmacology and site-specific microinjections to assess the relative contribution of the CRF1R and CRF2R receptors within the mPFC in modulating binge-like ethanol intake in the DID paradigm. Results from this project will advance our understanding of the neural mechanisms underlying binge-like ethanol intake, as well as characterize the potential for specific components of the mPFC CRF system to serve as a therapeutic target for treatment of alcohol dependence.